US4196123A - Hybrid chorionic gonadotropin preparations and methods for stimulating ovulation using same - Google Patents

Hybrid chorionic gonadotropin preparations and methods for stimulating ovulation using same Download PDF

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US4196123A
US4196123A US05/962,385 US96238578A US4196123A US 4196123 A US4196123 A US 4196123A US 96238578 A US96238578 A US 96238578A US 4196123 A US4196123 A US 4196123A
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subunits
hcg
preparation
chorionic gonadotropin
hormone
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Eugenia Rosemberg
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]

Definitions

  • This invention relates to gonadotropins and gonadotropin therapy, more particularly to the use of particular gonadotropin materials in stimulating ovulation in females, and particularly to human chorionic gonadotropin materials.
  • Gonadotropic hormones e.g. follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are produced in the pituitary gland and control the function of both the ovaries and testes. After being secreted by the pituitary, under the influence of the hypothalamic gonadotropin releasing factor, FSH and LH circulate in the blood stream and thus are carried to and act on the ovaries or testes. Some of each of the hormones is removed from the blood by being metabolized and some is excreted in the urine. Chorionic gonadotropin (CG) is produced in the placenta and is excreted in the urine throughout pregnancy. Human chorionic gonadotropin (hCG), which is generally obtained by extraction from the urine of pregnant women, is commercially available, e.g., under the trade names Follutein and APL.
  • FSH follicle-stimulating hormone
  • LH luteinizing hormone
  • Gonadotropins have been found to be useful for many purposes in the treatment of both animals and humans.
  • Chorionic gonadotropin (CG) has been found to be particularly useful in treatment of various conditions of the gonads (ovaries and testes) in humans and lower mammals. For instance, administration of CG to lower animal species will induce stimulation of immature gonads.
  • Human chorionic gonadotropin (hCG) has generally been utilized in such work, since it is available commercially, and can be administered to other mammals.
  • HCG has been used for animal breeding purposes (e.g., the breeding of sheep, cattle, etc.). HCG has also been found useful in treating humans for: (1) induction of ovulation and pregnancy in the anovulatory infertile women; (2) treatment of female patients with disorders of the menstrual cycle; (3) treatment of threatened abortion; (4) treatment of female patients with luteal phase defects; (5) treatment of delayed adolescence; (6) treatment of selected causes of hypogonadotropic hypogonadism (males and females); (7) treatment of prepubertal cryptorchidism not due to anatomical obstruction; and (8) treatment of oligospermia.
  • LH luteinizing hormone
  • FSH follicle stimulating hormone
  • hCG human chorionic gonadotropin
  • ovarian hyperstimulation which may evidence itself in enlargement of the ovaries, ascites (fluid in the peritoneal cavity) hypotension, hydrothorax (fluid in the pleural cavity), thrombophlebitis, and the development of ovarian cysts as well as other disorders. See generally, Rosemberg, supra, at 201-57. Again, close control of dosage and monitoring of hormone levels have reduced the occurrence of such problems, but have not solved them.
  • the invention herein comprises hybrid hormone preparations comprising a product of admixture of ⁇ -chorionic gonadotropin subunits and ⁇ -chorionic gonadotropin subunits, wherein the molar ratio of ⁇ subunits to ⁇ subunits is greater than 1.6:1.
  • a method for stimulating ovulation in female mammals comprises administering a hybrid hormone preparation comprising a product of admixture of ⁇ -CG subunits and ⁇ -CG subunits wherein the ratio of ⁇ subunits to ⁇ subunits is greater than about 0.3:1.
  • FIG. 1 is a graph illustrating the biological effect of certain embodiments of this invention over a period of time following administration.
  • a hybrid hormone preparation having a biological effect is obtained when CG subunits have ⁇ / ⁇ ratios greater than 1:1, e.g. advantageously about 1.6:1 to about 10:1, are admixed.
  • the ⁇ / ⁇ ratio is in the range of from about 2:1 to about 8:1 with the ratio of about 2.5:1 to about 5:1, e.g. about 3:1, being particularly preferred.
  • the preparation is preferably administered intramuscularly to obtain the desired biological effect.
  • the preparation of this invention is used for the treatment of female mammals to stimulate ovulation, the danger of overstimulation and multiple pregnancies is significantly reduced. Reduction of overstimulation will be effected by using any preparation in accord with the invention having an ⁇ / ⁇ ratio greater than about 0.3:1, preferably greater than 1:1.
  • the hybrid hormone preparation of this invention reduces the likelihood of overstimulation of the ovaries and, thus, the risk of multiple pregnancies, it is believed that this is due at least in part to a number of factors.
  • One factor is believed to be the lower potentiation of hormone effect because the preparations of this invention generally contain more ⁇ subunits than ⁇ whereas commercial hCG contains more ⁇ subunits than ⁇ subunits.
  • the hormone preparations in this invention are administered intramuscularly, their metabolic degradation will result in an excess of free ⁇ -hCG over ⁇ -hCG subunits.
  • ⁇ -hCG subunit corresponds to the molecular structure in the complete hCG unit which is primarily responsible for the biological activity of hCG, it is believed that with less ⁇ -hCG reaching the ovary, the likelihood of potentiation of hCG effect which results in ovarian overstimulation will be diminished. Another beneficial factor results from the fact that the product of the present invention has a shorter half life in the blood stream than commercial hCG preparations, and thus the period of time over which excess stimulation can occur is reduced.
  • hCG human chorionic gonadotropin
  • hCG is defined as any hCG that is obtained by extraction and is derived from a human source, whether further purified as in the case of hCG Canfield or not as in the case of commercial hCG.
  • the ⁇ and ⁇ subunits of hCG were obtained from Dr. Robert Canfield, Department of Medicine College of Physicians and Surgeons, Columbia University, New York, New York.
  • the ⁇ and ⁇ subunits were prepared by the method described in the Morgan, et al. reference, supra, "Properties of Subunits of Human Chorionic Gonadotropins," Endocrinology, 94, 5, p. 1601 (June 1974), which is hereby incorporated by reference.
  • the ⁇ and ⁇ subunits are readily obtained from Dr. Canfield or from the National Institute of Health.
  • the ⁇ and ⁇ subunits of hCG were hybridized or recombined by admixing the subunits in various ratios.
  • the molecular weight of native hCG, and of ⁇ and ⁇ -hCG used in making calculations were:
  • each subunit used for recombination or hybridization is shown in column A; the corresponding moles are shown in column B.
  • the combined weight ( ⁇ + ⁇ , column C) was dissolved in 0.01 M phosphate buffer, pH 7.0 (volumes of buffer shown in column D) mixed by Vortex, and incubated for 16 hrs. at 37° C. After incubation, each sample was diluted to the volume of buffer shown in column E to prepare stock solutions with concentrations of 10 or 20 ⁇ g of the combined weight of ⁇ + ⁇ -hCG per ml of buffer. After recombination, no attempts were made to remove "free" subunits by gel filtration.
  • the RIA's were performed following the double antibody procedure described by Odell et al, J. Clin. Invest., 46, p. 248 (1967).
  • the RIA's used were: (1) a homologous hCG system, utilizing a purified preparation of hCG as label, and an anti hCG serum used at a final dilution of 1:200,000; (2) an ⁇ -hCG subunit system utilizing ⁇ -hCG as label, and an anti ⁇ -hCG serum used at a final dilution of 1:400,000, and (3) ⁇ -hCG subunit system utilizing highly purified hCG as label and an anti- ⁇ -hCG serum at a final dilution of 1:180,000.
  • 125 I was used for iodination of antigens following the procedure described by Odell, et al.
  • Table 3 presents the potency of the ⁇ and ⁇ -hCG subunits, and of the various ⁇ and ⁇ -hCG recombinations in terms of (1)--the purified hCG preparation (Canfield's), and (2)--of the International standard of hCG (hCG-IS). It should be noted that the slope of ⁇ -hCG was non-parallel to that of the other preparations, however, the slopes of all other preparations tested were not significantly different from each other. Hybridizations A to C (1:1 to 2:1) were twice as potent as hCG Canfield: D (3.2:1) was 1.6 times, and E (5:1) was 1.4 times more potent than hCG Canfield: F (8.1:1) was equipotent to hCG Canfield.
  • Table 4 presents the ⁇ and ⁇ content of the two hCG preparations of the ⁇ and ⁇ -hCG subunits, and of the various hybrid hCG preparations studied in the ⁇ and ⁇ -hCG RIA systems.
  • Table 5 is a summary of the RIA's and shows the specific activity (Relative Potency) of the preparations in the homologous hCG system expressed in terms of hCG Canfield and hCG-IS (data from Table 3), and the percent columns 1 and 2 (data from Table 4) of ⁇ and ⁇ -hCG subunits contained in each hybrid measured in the ⁇ and ⁇ -hCG systems, as well as their respective ⁇ / ⁇ and ⁇ / ⁇ ratios (columns 3 and 4). It should be noted that the ⁇ / ⁇ ratios increase as the ⁇ content of the hybrids increases.
  • 10,000 IU's of commercial hCG contains 290 ⁇ g (or 0.0162 moles) of ⁇ -hCG and 900 ⁇ g (or 0.03 moles) of ⁇ -hCG; 5,000 IU's of commercial hCG contain half these amounts, i.e.,: 145 g (0.0081 moles) of ⁇ -hCG, and 450 ⁇ g (0.015 moles) of ⁇ -hCG.
  • the international unit is defined as the specified biological activity contained in a defined weight of a current international standard.
  • the standard is the material as it exists in the ampoules; the "material” thus includes the active ingredients together with all the other constituents such as moisture and in some instances carrier and buffer salts.
  • Hormone preparations in accord with my invention are also advantageously packaged for use in ampoules containing the equivalent to 5,000 to 10,000 IU's of hCG-IS activity. Based on the data with respect to activity of the hybrid preparations of my invention, examples of ampoules of hybrid preparations in accord with the present invention would be prepared containing ⁇ and ⁇ subunits as follows (See Table 6A and 6B):
  • the ⁇ and ⁇ hCG subunits should contain no more than 5% contamination with native hCG.
  • Pharmacological preparations in accord with my invention may also be produced as, for instance, tablets, pills or capsules for oral administration; suppositories, for example, for intravaginal administration; ampoules of material as noted above for injection, for example, intramuscularly or intravenously; etc.
  • Pharmaceutically acceptable, organic or inorganic, solid or liquid carriers may be used, suitably for oral or parenteral administration, in manufacturing the preparation.
  • Gelatine, lactose, starch, magnesium stearate, micronized silica gel, cocoa butter, talc, vegetabilic and animalic fats and oils, vegetabilic rubber and polyalkylene glycol and other known carriers for pharmaceuticals are all suitable for manufacturing preparations of said compounds.
  • Preparations for parenteral use include an ampoule of a sterile solution or suspension with water or other pharmaceutically acceptable liquid as the carrier therefor, or an ampoule of sterile powder for dilution with a pharmaceutically acceptable liquid.
  • Hormone preparations in accord with my invention are useful for many purposes in the treatment of both animals and humans. For instance, administration of hormone preparations of this invention to lower animal species will induce stimulation of immature gonads (ovaries and testes). Thus, these preparations are a very important tool in the in vivo as well as the in vitro (radioassay) study of the processes involved in reproduction and in the study of the immunological and biological characteristics of the hCG molecule.
  • the hormone preparations of this invention can also be utilized for animal breeding purposes (e.g., the breeding of sheep, cattle, etc.). Preparations having ⁇ / ⁇ ratios greater than 0.3:1 are useful although ratios greater than 1:1 and less than about 5:1 are particularly useful for this purpose with the preparation having an ⁇ / ⁇ ratio of about 3:1 being most preferred.
  • the hormone preparations of this invention are also useful in treating infertility in monkeys used for research purposes in the Primate Centers in the United States and elsewhere. ⁇ / ⁇ ratios preferred for this purpose are the same as above.
  • hormone preparations of my invention are also useful in treating humans, for example, for:
  • hypogonadotropicHypogonadism males and females
  • the hormone preparations of my invention are usually administered by the intramuscular route.
  • hormone preparations with ⁇ / ⁇ ratios greater than 1:1 and less than about 5:1 are preferred. The most preferred ratio will be about 3:1.
  • the hybrid should be administered at a dose equivalent to 5,000 or 10,000 IU hCG-IS, one day after the administration of the last dose of menotropins. Menotropins should be administered at daily dosages of 75 to 150 IU of FSH activity for 6 days. Treatment should be started 7 days prior to the administration of the hybrid.
  • the preparation should preferably be administered at a daily dose equivalent to 1,000 IU hCG-IS from day 3 to 9 of the menstrual cycle.
  • the preparation should preferably be administered at a daily dose equivalent to 1,000 IU hCG-IS from day 16 to 24 of the menstrual cycle.
  • the preparation should preferably be administered at a daily dose equivalent to 2,000 IU hCG-IS for the length of time necessary to control the condition.
  • the preparation should preferably be administered at a daily dose equivalent to 1,000 IU hCG-IS activity for a period of 15 to 20 days or longer depending on clinical response.
  • the preparation should preferably be administered at a dose equivalent to 2,000 to 3,000 IU hCG-IS every other day for a period of two to three months.
  • the preparation should preferably be administered at a dose equivalent to 1,000 IU hCG IS three times weekly for 3 weeks. If this course is not effective, another should begin one month later, administering the hybrid at a dose equivalent to 2,000 IU hCG-IS three times weekly for a period of three weeks.
  • the preparation should preferably be administered at a dose equivalent to 2,000 to 3,000 IU hCG-IS three times weekly for periods of 3 to 6 months or longer according to clinical response.
  • the mouse uterine weight assay was used to measure the biologic activity of hCG-Canfield, hCG-IS and of the various recombinations of ⁇ and ⁇ -hCG subunits.
  • the bioassay employs as the end-point the uterine weight increase in 21 day-old intact Swiss albino rats.
  • the bioassay method was carried out as previously described by Rosemberg et al, J. Clin. Endrocrinol. Metab., 22, p. 953, (1962), which is hereby incorporated by reference.
  • the total dose for injection of each material was prepared from stock solutions (for preparation of stock solutions refer to Table 1 and discussion above). The solution was such that the total fluid injected into each mouse was 2.5 ml. The total dose was divided into 5 single subcutaneous injections of 0.5 ml each, given during the course of 3 days. Autopsies were carried out about 72 hours after the first injection. The uteri were cut out at the insertion of the oviducts and immediately distal to the cervix uteri; they were dissected, pressed between filter papers and weighed at once in a Roller-Smith torsion balance. Potency estimates were calculated by standard statistical methods for valid parallel line graded dose assays.
  • hCG-IS was tested in the MUWtA in order to show the effect of varying dose levels of hCG in this bioassay system.
  • hCG Canfield 1.2 and 2.5 ng
  • hCG-IS 156 and 325 ng
  • the hybrid preparations were tested at 1.2 and 2.5 ng (doses were based on the combined weight of ⁇ + ⁇ -hCG used for hybridization). The results of the biological testing are presented in Tables 7A and 7B.
  • Tables 7A and 7B show the specific activity (Relative Potency) of hCG-IS, and of the various hybrid preparations in terms of purified hCG Canfield. Biologic activity was restored when complementary subunits ⁇ and ⁇ of hCG were hybridized. The greatest biologic activity was attained with hybrids containing ⁇ / ⁇ ratios of 1:1 and 2:1, and 3.2:1. These hybrids were equipotent to hCG Canfield. Hybrids containing ⁇ / ⁇ ratios of 5:1 showed about 60% of the biologic activity present in hCG Canfield. Hybrids containing ⁇ / ⁇ ratios of 8:1 showed about 40 (+)% of the biologic activity present in hCG Canfield. There were no significant differences in the specific activities when the vehicle used for administration of the preparations was PBS (phosphate buffer solution) buffer (Table 7A) or 0.9% saline (Table 7B).
  • PBS phosphate buffer solution
  • hCG Canfield purified native hCG
  • hCG-IS which has a potency equivalent to commercial hCG. Therefore, the hybrid preparations of my invention can be at least 6 (+) times more potent than commercial hCG and hCG-IS.
  • Table 8 provides a tabulation of the characteristics of the assay, i.e. the value of individual slopes and of the index of precision of the assay ( ⁇ ).
  • the dosages used were calculated to exceed the minimal dose (MD) causing an increase in uterine weight singnificantly different from controls.
  • hCG Canfield For hCG Canfield, the amount given was 7 times higher than its MD dose.
  • the dosages used for all other preparations i.e.: hCG-IS and hCG hybrids were calculated to equal or exceed that of hCG Canfield (biologic potency). The doses used are tabulated in Table 10 below.
  • Table 11 shows the end organ response (uterine weight/body weight ratio) at each time interval after the administration of a single dose of each preparation. Except for hCG Canfield, all other preparations elicited a significant increase in uterine weight 16 hours after injection. All preparations elicited a sustained increase in uterine weight from 24 to 62 hours after injection.
  • FIG. 1 is a graph illustrating the effect of the administration of the hybrid preparations as a percent of the effect elicited by hCG-IS shown in Examples 8-14.
  • FIG. 1 shows that from 16 to 44 hours after injection, all hCG hybrids except Curve A ( ⁇ / ⁇ , 1:1) and Curve B ( ⁇ / ⁇ , 8:1), elicited a response higher than that of hCG-IS.
  • hCG Canfield (not shown) showed a higher response from 24 to 44 hours after injection.
  • the effect of hybrids Curve E ( ⁇ / ⁇ , 3.2:1) and Curve B ( ⁇ / ⁇ , 8:1) and of hCG Canfield was increased.
  • all preparations showed a sharp decrease in activity compared to that of hCG-IS.
  • a pharmacological preparation of the hybrid hormone of this invention is prepared for injection in the following manner.
  • ⁇ -hCG subunits and ⁇ -hCG subunits are combined in the desired molar ratio, for example, 3 m moles ⁇ -hCG/1 m mole ⁇ -hCG, and dissolved in 0.01 M phosphate buffer, pH 7.0. At least one ml of buffer should be used for each mg of combined weight of the subunits.
  • the mixture is mixed by Vortex and incubated at 37° C. for 16 hours after which the mixture is diluted by 100 fold and the recombined material is lyophilized.
  • Lactose in an amount of from 0.1 to 1.0% of the dilute solution can be added prior to lyophilization to aid in redissolving.
  • the lyophilized material is then weighed into sterile ampoules in accord with Tables 6A and 6B above. For the 3:1 ratio above, 1414 ⁇ g are weighed for a 10,000 IU hCG-IS ampoule, and 707 ⁇ g are weighed for 5000 IU hCG-IS ampoule, for example.
  • the material in ampoules is dissolved in 0.9% sterile saline using 1 cc of saline for each 1000 IU in the ampoule.
  • the proper amount of preparation can be withdrawn from the ampoule with a syringe for injection, for example, intramuscularly or intravenously.
  • hormone preparations of this invention i.e., hybrids of hCG-subunits
  • the hormone preparations of this invention represent a hormone that is distinct from commercially available hCG preparations obtained by extraction procedures of native hCG from the urine of pregnant women.
  • the difference between commercial hCG and hCG hybrid preparations of this invention include the following:
  • Commercial hCG apparently is a mixture of whole or intact hCG molecules and subunits where the ratio of ⁇ to ⁇ is substantially less than one, whereas the hybrid hormone preparations of this invention contain ratios of ⁇ to ⁇ subunits greater than one.
  • the biological activity of the hybrid hormone preparations of this invention can be 6 or more times greater than that of commercial hCG.
  • the biological effect at the ovarian level of the hybrid hormone preparations of the invention is more rapid than that of commercial hCG, which is probably due to a lower circulatory half-life of the hybrid hormone preparations than that of commercial hCG.

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US05/962,385 1978-11-20 1978-11-20 Hybrid chorionic gonadotropin preparations and methods for stimulating ovulation using same Expired - Lifetime US4196123A (en)

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US05/962,385 US4196123A (en) 1978-11-20 1978-11-20 Hybrid chorionic gonadotropin preparations and methods for stimulating ovulation using same
JP50210879A JPS55500899A (de) 1978-11-20 1979-11-16
PCT/US1979/000992 WO1980001040A1 (en) 1978-11-20 1979-11-16 Chorionic gonadotropin preparations and methods for using same
DE7979901651T DE2966939D1 (en) 1978-11-20 1979-11-16 Chorionic gonadotropin preparations and methods for using same
IT27399/79A IT1127248B (it) 1978-11-20 1979-11-19 Preparazioni gonadotropiniche corioniche e metodi per impiegarle
CA340,123A CA1128858A (en) 1978-11-20 1979-11-19 Chorionic gonadotropin preparations and methods for using same
EP79901651A EP0020649B1 (de) 1978-11-20 1980-06-03 Chorionische gonadotropin-zusammensetzungen und verfahren zu deren verwendung

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Cited By (12)

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US4255420A (en) * 1978-12-29 1981-03-10 Veb Berlin-Chemie Hormone combination and method for stimulation of ovulation
US4297343A (en) * 1977-10-11 1981-10-27 Behringwerke Aktiengesellschaft Contraceptive agent
EP0089218A2 (de) * 1982-03-15 1983-09-21 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JAPAN CHEMICAL RESEARCH CO., LTD Verfahren zur Reinigung von menschlichem Choriongonadotropin
US4556555A (en) * 1985-01-25 1985-12-03 North Carolina State University Process for the immunological neutering of animals
US4966753A (en) * 1987-08-18 1990-10-30 Molecular Rx, Inc. Immunotherapeutic methods and compositions employing antigens characteristic of malignant neoplasms
US4970071A (en) * 1985-01-18 1990-11-13 Mcmichael John Immunotherapeutic methods and compositions employing antigens characteristic of non human malignant neoplasms
WO1991001747A1 (en) * 1989-07-28 1991-02-21 Novo Nordisk A/S Method of treating infertility or sub-fertility in adult men, and the use of preparations in the method.
EP0537154A1 (de) * 1990-04-05 1993-04-21 Hygeia Sciences Ltd Nachweisverfahren für den totalgehalt an gonadotropen alpha-peptidketten.
US5484767A (en) * 1989-12-04 1996-01-16 Khan; Shafig A. Substantially pure steroidogenesis inducing protein and uses thereof
US6096318A (en) * 1973-05-07 2000-08-01 The Ohio State University Antigenically modified HCG polypeptides
US6660717B1 (en) * 1998-12-01 2003-12-09 Akzo Nobel, N.V. Folliculogenesis
WO2004069271A1 (en) * 2003-02-07 2004-08-19 Austria Wirtschaftsservice Gesellschaft mit beschränkter Haftung Use of human chorionic gonadotropin in the treatment in the treatment of symptoms caused by endometriosis

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US6361992B1 (en) 1996-05-08 2002-03-26 The United States Of America As Represented By The Department Of Health And Human Services Thyroid stimulating hormone superagonists
AU2013296709B2 (en) 2012-07-30 2018-03-08 Trophogen Inc. Glycoprotein hormone long-acting superagonists
US10457713B2 (en) 2012-07-30 2019-10-29 Trophogen, Inc. Glycoprotein hormone long-acting superagonists
CA2929561A1 (en) 2013-11-05 2015-05-14 Trophogen Inc. Glycoprotein hormone long-acting superagonists

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IT1057895B (it) * 1975-02-17 1982-03-30 Serono Lab Gonadotropina corionica umana parzialmente desalinizzata per indurre l'ouvulazione

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096318A (en) * 1973-05-07 2000-08-01 The Ohio State University Antigenically modified HCG polypeptides
US4297343A (en) * 1977-10-11 1981-10-27 Behringwerke Aktiengesellschaft Contraceptive agent
US4255420A (en) * 1978-12-29 1981-03-10 Veb Berlin-Chemie Hormone combination and method for stimulation of ovulation
EP0089218A2 (de) * 1982-03-15 1983-09-21 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JAPAN CHEMICAL RESEARCH CO., LTD Verfahren zur Reinigung von menschlichem Choriongonadotropin
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IT1127248B (it) 1986-05-21
EP0020649B1 (de) 1984-04-25
WO1980001040A1 (en) 1980-05-29
IT7927399A0 (it) 1979-11-19
CA1128858A (en) 1982-08-03
EP0020649A4 (de) 1982-03-03
JPS55500899A (de) 1980-11-06
EP0020649A1 (de) 1981-01-07
DE2966939D1 (en) 1984-05-30

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